Marine organisms are a rich source of compounds with unprecedented chemical structures and biological activity. My long-term research goals are to isolate new biologically active compounds from marine organisms that can be used as molecular probes or drug leads relevant to human diseases. The overall objective of this research proposal is to generate a pilot-scale library of marine natural products with "drug like" properties. The specific hypothesis of this proposal is that we can exploit the amphiphilic nature of most biological active compounds (cytotoxic and non-cytotoxic) and the separation efficiency of polymeric resin to isolate compounds with a high probability of exhibiting in vitro and in vivo activity. The hypothesis is based on the following observations. First, by necessity, most bioactive compounds are required to be at least partially soluble in both hydrophilic and hydrophobic environments in order to reach the intended site of their activity and consequently are neither extremely polar nor non-polar in character (intermediate polarity). Second, crude organic extracts of marine organisms are comprised largely of water soluble salts, proteins and carbohydrates and very non-polar fats and steroids. Third, the use of the polymeric resin to fractionate the crude extract, instead of traditional silica based stationary phases, results in the efficient separation of biologically active compounds of intermediate polarity from the polar and non-polar compounds. The specific aims of this proposal are to 1) make additional targeted collections of marine organisms, 2) concentrate compounds from the crude extract with a high potential for being biologically active, and 3) isolate and characterize the "drug-like" compounds from the medium polarity fractions. The compounds provided to the Molecular Libraries Screening Center Network (MLSCN) will be accompanied by analytical purity and structural elucidation data together with record of the organism's collection and isolation scheme to permit re-isolation of the compounds. Achieving the specific aims outlined in this proposal will allow the generation of a structurally diverse "drug-like" marine natural products library that can be used by the MLSCN for high throughput screening to explore function at the molecular, cellular, and in vivo level to treat diseases. This study is also likely to yield many previously reported compounds of undetermined activity or mechanism that can be added to the MLSCN Library for screening. [unreadable] [unreadable] [unreadable]